Nearly four thousand cases of acute lymphoblastic leukemia (ALL) occur each year in this country. The majority of these develop in children under the age of 19 making it the most common form of childhood cancer. Fortunately, with an 80% survival rate, ALL is also among the most treatable forms of cancer. However, childhood cancer survivors face long-term health complications as the result of treatment. New treatments are required that do not decrease the quality of life of cancer patients long-term. Most likely these treatments will involve the use of targeted cancer therapeutics as this approach has had recent success. The development of targeted therapeutics necessarily requires an understanding of the molecular mechanisms that contribute to cancer. A recent study identified activating mutations in NOTCH1 in more than 50% of T-lineage ALL patients suggesting that NOTCH1 may be a valid therapeutic target. Given the importance of this pathway in T-ALL additional studies to understand the genetic mechanisms that synergize with NOTCH1 would be beneficial in designing more effective treatments. It has been proposed that the prevalence of NOTCH1 mutations in T-ALL is due to the role of the Notch pathway in the regulation of hematopoietic stem cells. Little is known about the genetic mechanisms that act differentially to transform stem cells and committed progenitor cells. This is mainly due to the inability to determine the biological state of the cell that initiates a tumor. Our recent work has produced a Sleeping Beauty (SB) transposon system that can be used to perform forward genetic screens in mice to identify cancer genes. We propose a series of experiments using a Cre-inducible SB system to address two fundamental questions in the genetics of T-ALL. The fist aim seeks to identify mutations that accelerate lymphomas induced by constitutive Notch signaling. The second aim will utilize the Cre- inducible SB transposon system to induce lymphomas by mutagenizing hematopoietic stem cells or committed T-cell progenitors. In both cases mutations found in tumors will be tagged by transposons allowing us to rapidly identify the genes involved in each process. Genes that are mutated in SB-induced lymphomas can quickly be evaluated for a potential role in human cancer. PUBLIC HEALTH RELEVANCE: Nearly four thousand cases of acute lymphoblastic leukemia (ALL) occur each year in this country. The majority of these develop in children under the age of 19 making it the most common form of childhood cancer. Activating mutations in NOTCH1 are found in more than 50% of T-lineage ALL patients. Given the importance of this pathway in T-ALL additional studies to understand the genetic mechanisms that synergize with NOTCH1 would be beneficial in designing more effective treatments.